舘 佳彦

AIM: To investigate the characteristics and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Atz/Bev) who achieved a complete response (CR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). METHODS: A total of 120 patients with Eastern Cooperative Oncology Group performance status (PS) 0 or 1 and Child-Pugh A at the start of Atz/Bev treatment were included. Barcelona Clinic Liver Cancer stage C was recorded in 59 patients. RESULTS: The CR rate with Atz/Bev alone was 15.0%. The median time to CR was 3.4 months, and the median duration of CR was 15.6 months. A significant factor associated with achieving CR with Atz/Bev alone was an AFP ratio of 0.34 or less at 3 weeks. Adding transarterial chemoembolization (TACE) in the six patients who achieved a partial response increased the overall CR rate to 20%. Among the 24 patients who achieved CR, the median progression-free survival was 19.3 months, the median overall survival was not reached, and 14 patients (58.3%) were able to discontinue Atz/Bev and achieve a drug-free status. Twelve of these patients developed progressive disease (PD), but eleven successfully received post-PD treatments and responded well. CONCLUSIONS: Achieving CR by mRECIST using Atz/Bev alone or with additional TACE can be expected to offer an extremely favorable prognosis.

OBJECTIVES: We set out to predict whether nonsurgical treatment is likely to succeed in removing pancreatic stones in a given patient and also to determine an optimal maximal number of extracorporeal shock wave lithotripsy (ESWL) sessions for treatment of pancreatolithiasis in that patient. MATERIALS AND METHODS: We ascertained the number of ESWL sessions for each of 164 patients undergoing that treatment for pancreatolithiasis between 1992 and 2020. Median follow-up duration was 31 months (range, 0-239), median age was 58 years (22-83), and the male to female ratio was 5.1:1.0. Patients were divided into 2 groups based upon an optimal maximal number of ESWL sessions determined by receiver operating characteristic analysis. RESULTS: Total stone clearance was achieved in 130 of 164 patients (79%). The median number of ESWL sessions was 3 (1-61). Receiver operating characteristic analysis determined 7 to be the optimal maximal number of sessions. Complete clearance was more frequent (87%) among the 131 patients requiring 7 or fewer ESWL sessions than among the 33 undergoing more (48%, P < 0.001). Seventeen patients (52%) undergoing 8 or more sessions still had residual stones. CONCLUSIONS: If any pancreatic stones persist after 7 ESWL sessions, we recommend transition to medical or surgical treatments.

OBJECTIVES: We aimed to determine when a coexisting pseudocyst was likely to complicate the nonsurgical treatment of pancreatolithiasis. METHODS: We treated 165 patients with pancreatolithiasis nonsurgically between 1992 and 2020, including 21 with pseudocysts. Twelve patients had a single pseudocyst less than 60 mm in diameter. Pseudocysts in the other nine patients had diameters of at least 60 mm or were multiple. The locations of pseudocysts along the length of the pancreas varied from the area with stone involvement to the pancreatic tail. We compared the outcomes in these groups. RESULTS: We found no significant differences in pain relief, stone clearance, stone recurrence, or the likelihood of adverse events between pseudocyst groups or between patients with vs without pseudocysts. However, 4 of 9 patients with large or multiple pseudocysts required transition to surgical treatment (44%) compared with 13 of 144 patients with pancreatolithiasis and no pseudocyst (9.0%) (P=0.006). CONCLUSIONS: Patients with smaller pseudocysts typically underwent nonsurgical stone clearance successfully with few adverse events, similar to findings in patients with pancreatolithiasis and no pseudocysts. Pancreatolithiasis complicated by large or multiple pseudocysts did not cause more adverse events but was more likely to require transition to surgery compared with pancreatolithiasis without pseudocysts. In patients with large or multiple pseudocysts, early transition to surgery should be considered when nonsurgical treatment is ineffective.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor composed of myofibroblasts with inflammatory blood cell infiltration. It commonly occurs in the lungs and rarely in the esophagus. We herein report a valuable case of IMT originating in the esophagus. A 60-year-old Japanese woman with dysphagia had a large subepithelial lesion (SEL) in the cervical esophagus, which was 15 cm in length. Surgical resection was performed to confirm the pathological diagnosis and improve the symptoms. The postoperative diagnosis was IMT composed of multiple nodules. There was no recurrence or metastasis within one year after surgery.

BACKGROUND: Many guidelines for nonsurgical treatment of pancreatolithiasis suggest little guidance for patients with pancreatolithiasis who do not have abdominal pain. Some patients with pancreatolithiasis whom we have treated nonsurgically with extracorporeal shock-wave lithotripsy did not have abdominal pain, and we describe one of them here. METHODS AND RESULTS: A 42-year-old man complaining of an 8-kg weight loss over 6 months was admitted to a nearby hospital, where fasting blood sugar and hemoglobin A1c values were 500 mg/dL and 11.8%. Computed tomography showed stones in the head of the pancreas and dilation of the main pancreatic duct. He was referred to our hospital to be considered for nonsurgical treatment of pancreatolithiasis. His height and weight were 160 cm and 52 kg (body mass index, 20.31). No tenderness or other abdominal findings were evident. After obtaining informed consent for nonsurgical treatment despite absence of abdominal pain, we performed extracorporeal shock wave lithotripsy. Computed tomography showed disappearance of stones from the pancreatic head. At discharge, his weight had increased to 62 kg and hemoglobin A1c was 6.8%, though antidiabetic medication has since become necessary. CONCLUSION: We believe that nonsurgical treatment of pancreatolithiasis was helpful for this patient, and could improve exocrine and endocrine function in other patients without abdominal pain.

OBJECTIVE: Clinical guidelines consider abdominal pain an indication for nonsurgical treatment of pancreatolithiasis. We examined benefit from nonsurgically treating asymptomatic pancreatolithiasis. METHODS: We retrospectively reviewed 165 patients with pancreatolithiasis who underwent nonsurgical treatment between 1992 and 2020. Symptoms were absent in 41, while 124 had abdominal pain. In the asymptomatic group, the median follow-up duration was 8 months (range, 0-166 months), and the median age was 61 years (range, 32-80 years). In patients with pain, the median follow-up duration was 43 months (range, 0-293 months), while the median age was 57 years (range, 22-80 years). The male:female ratio was 3.6:1 for asymptomatic patients and 5.9:1 for those with pain. We compared treatment outcome, stone recurrence rate, and changes in pancreatic exocrine function (bentiromide- p -aminobenzoic acid test results) between groups. RESULTS: Nonsurgical treatment for patients with asymptomatic pancreatolithiasis had a 63% stone clearance rate, lower than 84% for symptomatic pancreatolithiasis but comparable to outcomes at other institutions. Pancreatic exocrine function values during the year after treatment were mean, 52% (standard deviation, 16%) in the asymptomatic group, similar to mean, 57% (standard deviation, 17%) in the symptomatic group. CONCLUSIONS: Nonsurgical treatment in asymptomatic pancreatolithiasis may preserve pancreatic exocrine function as well as in symptomatic pancreatolithiasis.

OBJECTIVES: While chronic pancreatitis associated with pancreatolithiasis presents with pain, exocrine and endocrine pancreatic functions worsen with time. We examined outcomes of nonsurgical treatment. METHODS: Between 1992 and 2020, we treated pancreatolithiasis nonsurgically in 165 patients with chronic pancreatitis using extracorporeal shock wave lithotripsy alone or followed by endoscopic procedures. The mean follow-up duration was 49 months (standard deviation, 56 months) and the age was 56 years (standard deviation, 13 years). The male:female ratio was 5.1:1 (138 men, 27 women). We followed treatment results including relief of abdominal pain, stone clearance and recurrence, and pancreatic exocrine function (bentiromide-p-aminobenzoic acid testing). RESULTS: Treatment relieved pain in 117 of 124 patients (94%). The overall stone clearance was achieved in 130 of 165 patients (79%). Stones recurred during follow-up in 50 of 130 patients (38%). One fifth of recurrences were early, often involving stricture of the main pancreatic duct. After 1 year, 65% of the patients had improved or stable exocrine function. CONCLUSIONS: Nonsurgical stone removal usually improved symptoms and preserved pancreatic exocrine function. Nonsurgical treatment with extracorporeal shock wave lithotripsy followed by endoscopic treatment if needed is useful as initial management for pancreatolithiasis.

INTRODUCTION: Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. METHODS: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. RESULTS: The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child-Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5-13). The albumin-bilirubin (ALBI) score ranged from - 3.01 to - 0.45 (median - 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child-Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10-4 and 2.42 × 10-4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. CONCLUSION: Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. TRIAL REGISTRATION: UMIN registration no, 000038587.

BACKGROUND AND AIM: The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12 weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent. METHODS: In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen. RESULTS: Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching. CONCLUSION: Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis.

BACKGROUND: In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. METHODS: In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. RESULTS: Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. CONCLUSION: The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naïve, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

BACKGROUND AND AIMS: Real-time tissue elastography is a non-invasive method for measuring liver elasticity. However, there are no reports evaluating the value of real-time tissue elastography for liver fibrosis in hepatitis C virus-infected patients with sustained virological response. The aim of this study is to clarify the diagnostic performance of real-time tissue elastography in patients with sustained virological response. METHODS: In this prospective study, we enrolled 425 chronic hepatitis C patients who underwent liver biopsy: 118 patients with sustained virological response (45.8% women) and 307 patients with hepatitis C virus (51.1% women). The post-sustained virological response biopsy was performed 5.9 ± 1.8 years after the therapy. Liver fibrosis index measurements as assessed using real-time tissue elastography were performed on the same day of biopsy. RESULTS: The respective mean liver fibrosis index values for fibrosis stages F0, F1, F2, F3, and F4 were 2.82 ± 0.33, 2.90 ± 0.51, 3.06 ± 0.58, 3.65 ± 0.24, and 3.83 ± 0.65, respectively, in patients with sustained virological response. The diagnostic accuracies expressed as areas under the receiver operating characteristic curves in patients with sustained virological response were 0.776 for the diagnosis of significant fibrosis (≥F2), 0.885 for severe fibrosis (≥F3), and 0.860 for cirrhosis (F4), respectively. The optimum cut-off values liver fibrosis index were 3.14 for ≥F2, 3.24 for ≥F3, and 3.30 for F4 in patients with sustained virological response. CONCLUSION: Real-time tissue elastography is an acceptable method for predicting the severity of fibrosis in hepatitis C virus patients with sustained virological response.

Diseases associated with gallbladder wall thickening include benign entities such as adenomyomatosis of the gallbladder, acute and chronic cholecystitis, and hyperplasia associated with pancreaticobiliary maljunction, and also cancer. Unique conditions such as sclerosing cholecystitis and cholecystitis associated with immune checkpoint inhibitor treatment can also manifest as wall thickening, as in some systemic inflammatory conditions. Gallbladder cancer, the most serious disease that can show wall thickening, can be difficult to diagnose early and to distinguish from benign causes of wall thickening, contributing to a poor prognosis. Differentiating between xanthogranulomatous cholecystitis and gallbladder cancer with wall thickening can be particularly problematic. Cancers that thicken the wall while coexisting with benign lesions that cause wall thickening represent another potential pitfall. In contrast, some benign gallbladder lesions that can cause wall thickening, such as adenomyomatosis and acute cholecystitis, typically show characteristic ultrasonographic features that, together with clinical findings, permit easier diagnosis. In this review of the literature, we describe B-mode abdominal ultrasonographic diagnosis of gallbladder lesions showing wall thickening.

BACKGROUND: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. METHODS: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. RESULTS: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10-5; genotype 2 vs. 3, p = 3.28 × 10-5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10-5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10-5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10-18) patients. CONCLUSIONS: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Background/Aim: The frequency of hepatocellular carcinoma (HCC) in patients with good hepatic reserve function has been increasing in Japan along with the progression of antiviral therapies and aging of the society. We evaluated the usefulness of modified albumin-bilirubin (ALBI) grade as a tool for assessment of hepatic reserve function. Materials/Methods: We enrolled 6,649 naïve HCC patients treated from 2000 to 2017 and divided them into training (Ehime Prefecture group: E group, n = 2,357) and validation (validation group: V group, n = 4,292) cohorts. Child-Pugh classification and ALBI and modified ALBI (mALBI) grading were compared using with Japan Integrated Staging (JIS), ALBI-TNM (ALBI-T), and mALBI-T scores, which were calculated based on TNM stage and each assessment tool, retrospectively. Results: In the E group, Akaike's Information Criterion (AIC) and c-index values for mALBI-T (13,725.2/0.744) were better as compared to those of ALBI-T (13,772.6/0.733) and JIS score (13,874.7/0.720), with similar results observed in the V group (mALBI-T: 27,727.4/0.760; ALBI-T: 27,817.8/0.750; JIS: 27,807.5/0.748). Although there were some significant differences between the groups with regard to clinical background factors (age, etiology, tumor size, tumor number, treatment modalities), for all patients the AIC and c-index values of mALBI-T (45,327.1/0.755) were also better than those of ALBI-T (45,467.7/0.744) and JIS scores (45,555.8/0.739), indicating its superior stratification ability and prognostic predictive value in patients with HCC. Conclusion: The detailed stratification ability of mALBI grade for hepatic reserve function is suitable for the recent trend of HCC patients, while mALBI-T may provide a more accurate predictive value than existing total staging scoring systems.

Objectives: The effect of skeletal muscle fat deposition on the prognosis of patients with chronic liver disease remains unclear. Skeletal muscle fat deposition can be estimated by attenuation of skeletal muscle in Hounsfield units (HU) on computed tomography (CT). The aim of this retrospective cohort study was to investigate the association between skeletal muscle fat deposition assessed by skeletal muscle attenuation (SMA), and hepatocellular carcinoma (HCC). Methods: We enrolled 288 patients with chronic liver disease (139 men, 149 women mean age 67.5 ± 10.4 y hepatitis C virus, 239 hepatitis B virus, 17 without viral infection, 32 chronic hepatitis, 227 and cirrhosis, 61) who underwent liver biopsy and CT scanning between January 2013 and February 2017. The patients were divided into two groups based on SMA levels, with the cutoff value of 31 HU. We analyzed the effect of SMA on HCC development. Results: During the study follow-up period (median, 2.50 y range, 0.5–4.7 y), HCC was identified in 19 patients (7%). The cumulative incidence of HCC in patients with lower SMA (&lt 31 HU) was significantly higher than in patients with SMA ≥31 HU (P = 0.007). Cox proportional hazards regression analysis confirmed cirrhosis (hazard ratio [HR], 6.626 95% confidence interval [CI], 2.57–17.12 P &lt 0.001) and lower SMA (HR, 3.502 95% CI, 1.25–9.83 P = 0.017) as significant independent factors associated with HCC development in patients with chronic liver disease. Conclusions: Patients with cirrhosis and skeletal muscle fat deposition assessed by SMA had a higher risk for developing HCC.

BACKGROUND AND AIMS: Pruritus is one of the complications with chronic liver disease and markedly worsens quality of life. However, the current status of pruritus in chronic hepatitis C patients who have achieved a sustained virological response (SVR) has not been clarified sufficiently. The aim of this study was to investigate the predictors of pruritus in post-SVR patients treated with direct-acting antivirals (DAA). PATIENTS AND METHODS: In this retrospective study, we enrolled 110 hepatitis C patients with SVR who underwent serial shear wave elastography before DAA therapy and at the end of treatment. The severity of pruritus was evaluated using Kawashima's pruritus scores and a visual analog scale. RESULTS: The prevalence of pruritus before treatment and after SVR was 28.2 and 25.5%. Multivariate logistic regression analysis confirmed that a history of hepatocellular carcinoma [odds ratio (OR): 9.72; 95% confidence interval (CI): 2.05-46.15; P=0.004], high γ-glutamyl transpeptidase levels at baseline (OR: 5.77; 95% CI: 1.83-18.21; P=0.003), low serum albumin at the end of treatment (OR: 4.85; 95% CI: 1.31-17.99; P=0.018), and high liver stiffness measurement assessed by shear wave elastography at the end of treatment (OR: 3.16; 95% CI: 1.19-11.01; P=0.024) were significant independent factors associated with pruritus in patients who had achieved an SVR following DAA therapy. CONCLUSIONS: In chronic hepatitis C patients with SVR after DAA therapy, the incidence of pruritus is not uncommon. Liver stiffness measurement is useful for predicting the incidence of pruritus. Thus, even if SVR is achieved, patients with higher liver stiffness at the end of treatment must be monitored carefully for pruritus.

BACKGROUND AND AIM: Severe muscle volume loss is a recognized negative prognostic factor in patients with chronic liver disease. However, the effect of skeletal muscle fat deposition, referred to as myosteatosis on muscle volume loss remains unclear. The aim of this study was to investigate the relationships between myosteatosis and skeletal muscle volume loss. METHODS: We enrolled 362 patients with chronic liver disease (186 men, 176 women; mean age 68.4 ± 10.0 years, 94 with cirrhosis) who underwent liver biopsy and computed tomography scanning between January 2013 and February 2017. A transverse computed tomography image of each scan at the third lumbar vertebra was used to evaluate skeletal muscle tissues. RESULTS: Prevalence of skeletal muscle volume loss and myosteatosis were 36% and 82%, respectively. Of those with skeletal muscle volume loss, 93% have concomitant myosteatosis. Univariate analysis revealed that higher age, female, lower body mass index (BMI), higher serum albumin, lower alanine aminotransferase (ALT), lower gamma-glutamyl transpeptidase, lower total bilirubin, lower α-fetoprotein, lower skeletal muscle attenuation, and liver steatosis were significantly associated with skeletal muscle volume loss. Multivariate logistic regression analysis confirmed that lower BMI (odds ratio [OR] 5.26, 95% confidence interval [CI], 3.21-8.54; P < 0.001), presence of myosteatosis (OR, 2.82; 95% CI, 1.26-6.30; P < 0.001), lower ALT (OR, 2.04; 95% CI, 1.18-3.52; P = 0.010), and female (OR, 1.71; 95% CI, 1.04-2.28; P = 0.034) were significant independent factors associated with skeletal volume loss. CONCLUSIONS: Myosteatosis, low BMI, low ALT, and female are associated with skeletal muscle volume loss in patients with chronic liver disease.

Background &amp Aims: We investigated the correlation between histological characteristics and changes in liver stiffness (LS) in patients with sustained virological response (SVR) using acoustic radiation force impulse (ARFI) elastography. Methods: In this prospective study, we enrolled 176 hepatitis C patients with SVR who underwent ARFI elastography and liver biopsy before antiviral treatment, and serial ARFI elastography at the end of treatment (EOT) and at 24 weeks after the EOT. To compare the long-term changes in LS in patients with SVR using ARFI elastography, another group of 140 patients who had undergone paired biopsy after achieving SVR was included. Results: Mean LS values were 1.60±0.63 m/s, 1.48±0.56 m/s and 1.37±0.62 m/s at baseline, EOT and 24 weeks after EOT, respectively, P&lt .001. Higher inflammatory activity at baseline was associated with an improvement in LS at the EOT, with an odds ratio of 1.940. Significant fibrosis at baseline was associated with an improvement in LS at 24 weeks after the EOT, with an odds ratio of 2.617. Among patients in the paired biopsy group with baseline fibrosis stage identical to the ARFI group, LS values at 24 weeks after the EOT did not show any difference with values at 5 years after EOT. Conclusions: Pre-treatment histological characteristics influence LS reduction after SVR is achieved.

BACKGROUND AND AIM: Virologic failure of interferon-free therapy has been associated with Y93H mutation in the non-structure 5A region in hepatitis C virus (HCV) genotype 1b, and screening is recommended. A simple assay based on Q-Invader technology was developed for Y93H mutant screening to reduce cost and effort. The present study sought to compare two methods of detection of Y93H mutation and to evaluate the effect of Y93H mutation on response to interferon-free therapy. METHODS: Y93H mutation was examined in 258 patients with HCV genotype 1b using both direct sequencing analysis and the polymerase chain reaction (PCR)-Invader assay. Daclatasvir and asunaprevir or ledipasvir and sofosbuvir therapy was administered to 205 patients whose sustained virological responses (SVR) were checked. RESULTS: Hepatitis C virus was detected in 232 of 258 patients by direct sequencing and in 236 of 258 patients by the PCR-Invader assay. Forty of 231 cases were defined as Y93 mutation by direct sequencing, and 46 of 236 cases were defined as Y93 mutation by the PCR-Invader assay. SVR of patients who were Y93H by direct sequencing, Y93H by the PCR-Invader assay, and Y93H by both methods was 62.5%, 82.4%, and 50%, respectively. CONCLUSIONS: The sensitivity of the PCR-Invader assay was similar to that of direct sequencing analysis; however, the PCR-Invader assay had a better ability to detect minor strains. Combination of the two assays would improve prediction of the response to daclatasvir and asunaprevir, but Y93H mutation had little effect on SVR in ledipasvir and sofosbuvir therapy.

Background & Aims: Anti-hepatitis C virus (HCV) therapy by interferon (IFN)-free regimen with oral direct-acting antiviral drugs are tolerable in aged patients, with fewer adverse effects than IFN-based therapies. We investigated the efficacy and tolerability of an IFN-free anti-HCV therapy in extremely aged patients, as well as the survival benefit of sustained virologic response (SVR). Methods: Following IFN-free therapy with daclatasvir and asunaprevir, tolerability and SVR rate were compared between 115 HCV genotype 1-infected patients aged 80 years or older, 151 patients in their 70s (&gt;= 70 and &lt;80 years), and 115 patients under the age of 70. One-year mortality and morbidity in patients aged &gt;= 80 years were compared between SVR patients and propensity score-matched patients with persistent HCV infection. Results: The SVR rate was 96.5% in patients &gt;= 80 years, comparable to that in patients aged &gt;= 70 and &lt;80 years (95.4%) and patients aged &lt;70 years (93.9%). There were no differences in treatment discontinuation rate (2.6%, 1.3%, and 0.9%, respectively). One-year mortality was significantly lower in SVR patients (2.7%) than in patients with persistent HCV infection (15.3%, p = 0.0016). Whereas 1-year mortality due to liver related diseases was 8.1% in patients with persistent HCV infection who were aged a &gt;= 80 years, no SVR patients died from liver diseases within 1-year after the end of therapy. Conclusions: IFN-free therapy for HCV infection was associated with high tolerability and antiviral efficacy, even in patients aged 80 years. In addition, there seemed to be a survival benefit from the eradication of HCV in this population. Lay summary: IFN-free therapy with oral direct-acting antiviral drugs (daclatasvir and asunaprevir) for HCV infection showed similar tolerability and antiviral efficacy in patients aged &gt;= 80 years as in younger patients (patients aged &gt;= 70 and &lt;80 years and patients aged &lt;70 years), with an SVR rate over 90% and no severe adverse effects. There was a survival benefit from the eradication of HCV even in patients aged &gt;= 80 years. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background: Hepatocellular carcinoma (HCC) in patients with chronic hepatitis C can develop after sustained virological response (SVR) to antiviral therapy for HCV, that is, the eradication of HCV, and effective surveillance systems for HCC should be established for this population. We retrospectively evaluated the utility of three laboratory liver fibrosis indices (aspartate aminotransferase-platelet ratio index [APRI], FIB-4 index and Forns index) for identifying patients at low risk of HCC development after SVR, for whom the termination of surveillance for HCC can be considered. Methods: APRI, FIB-4 index and Forns index scores were calculated based on laboratory data prior to anti- HCV therapy and at 24 weeks after the end of anti-HCV therapy (SVR24) in 522 patients with SVR who continued surveillance for HCC after SVR. The associations between HCC development and laboratory indices at both points were analysed. Results: Twenty-one patients developed HCC after SVR during 2.3-24.4 years follow-up. Whereas HCC developed even in patients with low APRI or FIB-4 index scores, no patients with low Forns index scores developed HCC after SVR. These results were confirmed in a separate cohort of 309 patients who achieved SVR (HCC developed in 17 patients during 1.7-21.6 years follow-up). Conclusions: Forns index, especially assessed prior to anti-HCV therapy, was a useful laboratory liver fibrosis index for identifying patients at low likelihood of HCC after SVR. This index may be used as one of indicators to consider the termination of surveillance for HCC after the eradication of HCV.

Reactivation of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-positive patients treated with immunosuppressive or cytotoxic chemotherapy is well known and has emerged as an important clinical issue. The risk is low, but reactivation of HBV in HBsAg-negative patients after resolution of HBV infection also occurs; however, the clinical and virological characteristics remain somewhat unclear. We investigated HBsAg-negative patients who developed HBV reactivation during or after immunosuppressive or cytotoxic chemotherapy to clarify the clinical and virological features. Reactivation of HBV in 30 previously infected that is HBsAg-negative patients during or after immunosuppressive or cytotoxic chemotherapy was examined. Direct sequencing at the time of reactivation was used to evaluate 11 patients. The majority of patients had diffuse large B cell lymphoma treated by rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Fulminant hepatic failure developed in three patients, who did not survive. HBV subgenotypes A2/Ae (n = 1), B1/Bj (n = 2), and C2/Ce (n = 8) were detected. There were no significant differences in the prevalence of BCP/PC variants between HBV reactivation and acute self-limited hepatitis patient groups. BCP and PC variants were not associated with development of fulminant hepatic failure from HBV reactivation. The prevalence of HBV S region variants, including immune-escape mutants, among reactivation patients was significantly higher than that in acute self-limited hepatitis patients. Reactivation risk factors included male sex, advanced age, and hematological malignancy. HBV S gene immune-escape mutants were frequently found in the HBsAg-negative reactivation patients during or after immunosuppressive or cytotoxic chemotherapy.

BackgroundAcoustic radiation force impulse (ARFI) elastography is a non-invasive method for measuring liver stiffness. However, there are no reports evaluating the value of ARFI elastography for liver fibrosis in chronic hepatitis C patients with a sustained virological response (SVR). AimTo investigate the diagnostic performance of ARFI elastography for the assessment of liver fibrosis in hepatitis C virus (HCV) infected patients with an SVR. MethodsIn this prospective study, we enrolled 336 patients: 121 HCV patients with an SVR (44.6% women) and 215 patients with HCV (47.9% women). ARFI elastography measurements of all patients were performed on the same day of liver biopsy. ResultsThe diagnostic accuracies, expressed as areas under the receiver operating characteristic curves for ARFI elastography, in HCV patients with an SVR and those in patients with HCV were 0.818 and 0.875 for the diagnosis of significant fibrosis (F2), 0.909 and 0.888 for the diagnosis of severe fibrosis (F3), and 0.981 and 0.890 for the diagnosis of liver cirrhosis (F4), respectively. The optimum cut-off values for ARFI elastography were 1.26 m/s for F2, 1.31 m/s for F3 and 1.49 m/s for F4 in HCV patients with an SVR. The liver stiffness values were lower in patients with SVR compared with those in patients with HCV at the same stage of fibrosis. The liver stiffness values were affected by the necroinflammatory activity and the time after SVR. ConclusionAcoustic radiation force impulse elastography is an acceptable method for predicting the severity of fibrosis in patients with hepatitis C virus and a sustained viral response.

Aim: We investigated the characteristics and prognosis of patients with hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) to antiviral therapy for chronic hepatitis C virus (HCV) infection, namely, the eradication of HCV, according to surveillance status after SVR. Methods: In this multicenter study, liver function at HCC diagnosis and progression of HCC among patients with HCC diagnosed after SVR were compared. Outcomes were also investigated. Results: In patients not under surveillance after SVR, HCC was significantly more advanced at diagnosis, with tumors that were larger in size and of higher stage than in patients who continued under surveillance after SVR. Survival rates were significantly lower in patients not under surveillance (P &lt; 0.0001). Among patients who were under surveillance, those with a 6-month surveillance interval had larger and higher stage HCC than patients with a 3-month interval. Recurrence rates in patients with a 6-month surveillance interval were significantly higher than in patients with a 3-month surveillance interval (P = 0.0417). Conclusion: Lack of surveillance after SVR was obviously associated with more advanced HCC at detection, resulting in poor prognosis. More importantly, there may be a difference in the severity of HCC at diagnosis and prognosis based on the surveillance interval after SVR. Establishing guidelines how to survey patients with chronic hepatitis C after SVR is necessary.

Liver fibrosis remains an important risk factor for hepatocarcinogenesis in patients with chronic hepatitis C even after the eradication of hepatitis C virus (HCV). However, it is difficult to estimate liver fibrosis based on liver biopsy after the eradication of HCV. We investigated the ability of laboratory indices to predict liver fibrosis in patients with sustained virologic response (SVR) to antiviral therapy. Three laboratory liver fibrosis indices (aspartate aminotransferase-platelet ratio index (APRI), FIB-4 index, and Forns index) were calculated based on data at the time of initial pretreatment liver biopsy and at second liver biopsy performed approximately 5 years after SVR in 115 patients who underwent serial liver biopsies. The indices at the time of initial biopsy were compared to histological degree of liver fibrosis in initial biopsy, and laboratory indices at the time of second liver biopsy were compared to the degree of fibrosis in second biopsy. In both comparisons, there were significant increases in all 3 indices with the increase of liver fibrosis grade as assessed in liver biopsy specimens. All 3 indices at the time of second biopsy were able to predict moderate to advanced (METAVIR score F2-4) and advanced (F3-4) fibrosis on liver biopsy, with the area under the receiver-operating characteristics curve &gt;0.8 and the accuracy &gt;70%. All 3 laboratory indices of fibrosis accurately reflected liver fibrosis in patients with SVR for 5 years despite the normalization of serum liver transaminase activity and the lack of liver inflammation.

AimHepatocellular carcinoma develops even in some patients who achieve a sustained virological response following treatment for hepatitis C virus infection. This study investigated the relationship between changes in fibrosis, as assessed by sequential biopsies, and development of hepatocellular carcinoma in patients who achieved a sustained virological response for hepatitis C virus. MethodsWe enrolled 97 patients with sustained virological response who had undergone initial biopsies before therapy and sequential biopsies at an average of 5.81.9 years after the initial biopsy. Factors associated with hepatocellular carcinoma were retrospectively analyzed. ResultsThe liver fibrotic stage regressed in 44 patients (45%), remained stable in 47 patients (48%) and progressed in six patients (6%). The fibrotic stage significantly decreased, from 1.54 +/- 0.86 to 1.16 +/- 1.07 units. Hepatocellular carcinoma was identified in 12 patients (12.4%). The cumulative incidence of hepatocellular carcinoma in patients with progressive fibrosis was significantly higher than that in patients with regressed or stable fibrosis (P&lt;0.001). A Cox proportional hazards regression analysis confirmed that progressive fibrosis in sequential liver biopsies (hazard ratio [HR], 8.30; P=0.001) and low platelet counts before treatment (HR, 8.69; P=0.006) were significant independent factors associated with the development of hepatocellular carcinoma in patients with a sustained virological response. ConclusionProgressive fibrosis, assessed by sequential biopsies, was significantly correlated with development of hepatocellular carcinoma in patients who had achieved a sustained virological response for hepatitis C virus.

肝疾患における肝線維化の評価は、日常診療において重要である。特にC型慢性肝炎では、肝線維化の進行に伴いインターフェロン(IFN)治療抵抗性となることや、肝がんの発生率が増加するので、必須の臨床情報である。一般に、肝生検による肝線維化の評価がゴールドスタンダードとされている。肝線維化の判定には、わが国では新犬山分類を、欧米ではMETAVIRを基準に使用しており、F0(正常)〜F4(肝硬変)の5つに分類している。肝生検の短所として、診断医により結果がばらつく可能性と半定量的で連続性がなく、いわゆる、F3.5などと俗に呼ばれている境界病変など客観的に評価ができない問題点がある。さらに、侵襲的であるため出血や感染の副作用、またサンプリングエラーなどの問題がある。このため、非侵襲的で客観性の高い検査として、血清の線維化マーカーや推定式、および画像診断を用いた線維化の計測法の開発が進められてきた。超音波を使用した肝線維化の評価方法として、FibroScanがフランスのEchosens社から2003年に発表された。肝線維化の評価を中心に、肝発がん率やIFN治療効果との関連などについてFibroScanを利用した多くの検討がなされ、metaanalysisの報告も発表されている。わが国においても2011年9月より保険収載となり、FibroScanの利用が最も普及している方法の1つである。その後、liver stiffness measurementが可能な技術として、日立アロカメディカル社のReal-time Tissue Elastographyとシーメンス社のacoustic radiation force impulse(ARFI)を応用したVirtual Touch Tissue Quantification(VTTQ)が登場した。FibroScanが専用機であるのに対して、Real-time Tissue ElastographyとVTTQは汎用の超音波診断装置に搭載されており、BモードUSによる診断も可能である。Real-time Tissue Elastographyは、FibroScanより後に登場したので改良が多くなされているが、上記のような臨床データの蓄積は少ない。本稿では、C型慢性肝炎におけるReal-time Tissue Elastographyの有用性を解析し、日常診療を変えうる診断技術かどうか検討する。(著者抄録)

Hepatitis C virus (HCV) genotype 1a is rare in Japanese patients and the clinical characteristics of this genotype remain unclear. The interferon (IFN) sensitivity-determining region (ISDR) and single-nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) among patients with HCV genotype 1b are associated with IFN response, but associations among patients with genotype 1a are largely unknown. This study investigated the clinical characteristics of genotype 1a and examined whether genomic heterogeneity of the ISDR and SNPs of IL28B among patients with HCV genotype 1a affects response to combination therapy with pegylated-IFN-a2b and ribavirin. Subjects comprised 977 patients infected with HCV genotype 1, including 574 men and 412 women (mean age, 55.2 +/- 10.6 years). HCV was genotyped by direct sequencing of the 5'-untranslated region and/or core regions and confirmed by direct sequencing of the NS5A region. HCV genotypes 1a (n=32) and 1b (n=945) were detected. Twenty-three (71.9%) of the 32 patients with genotype 1a were patients with hemophilia who had received imported clotting factors. Prevalence of genotype 1a after excluding patients with hemophilia was thus 0.9%. Of the 23 patients with genotype 1a who completed IFN therapy, 11 (47.8%) were defined as achieving sustained virological response. Factors related to sustained virological response by univariate analysis were IL28B and ISDR. In conclusion, HCV genotype 1a is rare in Japan. The presence of IL28B genotype TT, and more than two mutations, in the ISDR are associated with a good response to IFN therapy in patients with HCV genotype 1a. J. Med. Virol. 84:438444, 2012. (C) 2011 Wiley Periodicals, Inc.